The Tennessee River appears on French maps from the late 17th century with the names "Caquinampo" or "Kasqui." Maps from the early 18th century call it "Cussate," "Hogohegee," "Callamaco," and "Acanseapi." A 1755 British map showed the Tennessee River as the "River of the Cherakees." By the late 18th century, it had come to be called "Tennessee," a name derived from the Cherokee village named Tanasi.

The river was a major highway to transport goods and explorers in the years when Tennessee was not yet settled. Some major towns that still exist today, and major ports at them were established by those who rode down the river, and settled along it.

The river has been dammed numerous times, primarily in the 20th century by Tennessee Valley Authority (TVA) projects since the 1930s.